1. Field of the Invention
The invention pertains to the field of pharmaceutical chemistry and provides a stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides.
2. State of the Art
The continued interest in the synthesis of 2'-deoxynucleosides and their analogues is reflected in their successful use as therapeutic agents in viral and cancerous diseases. A critical step in the synthesis of 2'-deoxynucleosides is the condensation of the nucleobase and carbohydrate to form the N-glycosidic bond. When the carbohydrate possesses a 2-hydroxy substituent, the substituent provides a substantial degree of 1,2-anchiomeric assistance, which facilitates stereoselective glycosylation. However, processes for synthesizing of 2'-deoxynucleosides are typically non-stereoselective and form a mixture of alpha and beta nucleosides.
Vorbruggen, et al., J. Org. Chem., 41, 2084 (1976) provided an outstanding development in the field of glycosylation and showed how nucleosides may be obtained from the Friedel-Crafts catalyzed reaction of a peracylated carbohydrate and silylated heterocycles in a solvent such as 1,2-dichloroethane or acetonitrile. But when this process was applied to the synthesis of 2'-deoxynucleosides, a 1:1 alpha to beta-anomeric mixture of nucleoside products was produced.
Some deoxynucleosides have been prepared in high yield from deoxyhalogenose with Friedel-Crafts catalysts, notably, 1-chloro-2-deoxy-3,5-di-p-toluoyl-alpha-D-erythro-pentofuranose; see, M. Hofer, Chem. Ber, 93, 2777 (1960). However, halogenoses are less stable thermally than peracylated carbohydrates and produce a 1:1 alpha to beta-anomeric mixture of nucleoside products. Walker, et al., Nucleic Acid Research, 12, 6827 (1984), used halogenose in condensation reactions to study the factors controlling the anomeric ratio of nucleoside products and found that beta-anomer nucleosides were formed exclusively from alpha-halo-carbohydrates via S.sub.N 2 displacement. The corresponding alpha-anomer nucleoside contamination was determined to result from the anomerization of alpha-halo carbohydrate to beta-halo carbohydrate before the S.sub.N 2 displacement reaction occurs. Walker, et al., found that by changing the solvent or catalyst higher yields of the desired beta-anomer nucleoside were produced.
R. P. Hodge et. al., J. Org. Chem., 56, 1553 (1991), described preparing pyrimidine and purine nucleosides containing deuterium at the C-1' position by the method described by Walker, et al. 1'-Deuterium-2'-deoxycytidine was prepared by reacting a carbohydrate and silylated cytosine derivative but the reaction gave poor yields. However, the yield was significantly improved when silylated uridine derivatives were used.
The synthesis of 2'-deoxy-2'-fluoronucleosides advanced rapidly when a procedure for synthesizing 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-D-arabinosyl bromide was made available; see Tann, et. al., J. Org. Chem., 50, 3644 (1985) and Howell, et. al., J. Org. Chem., 53, 85 (1988). It was discovered that 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-D-arabinosyl bromide did not anomerize in dry acetonitrile over extended periods. Therefore, high yields of beta-nucleosides could be obtained from 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-O-arabinosyl bromide via S.sub.N 2 displacement. Also, stereoselectivity of the nucleoside products could be achieved if either carbon tetrachloride or chloroform solvents was employed.
The formation of the N-glycoside bond in 2'-deoxy-2',2'-difluoronucleoside synthesis is much more difficult than in instances where the carbohydrate is 1,2-anchiomericly assisted or contains only 1 fluorine at the C-2 position. The traditional carbohydrate leaving groups, such as those used in the Vorbruggen condensation method, acetate, chloride and bromide, render the carbohydrate inactive. In order to overcome this problem, Hertel, U.S. Pat. No. 4,526,988, described a modified version of the Vorbruggen condensation method that relied on more reactive sulfonate leaving groups being attached to the carbohydrate to affect its reactivity. For example, hydroxy protected carbohydrates, such as 2-deoxy-2,2-difluoro-D-ribofuranose, containing methanesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate or 4-methoxybenzenesulfonate as a leaving group at the C-1 position, were reacted with a protected nucleobase at temperatures of 50.degree. C. to 220.degree. C., in the presence of a high boiling solvent, such as dimethylformamide, dimethylacetamide and hexamethylphosphoramide. Hertel teaches that when carrying out the glycosylation reaction at elevated pressures, any convenient inert solvent, such as ethers, halogenated alkanes, and aromatics, can be used since the elevated pressure eliminates the loss of low boiling inert solvents due to evaporation. However, at reaction temperatures from room temperature to 100.degree. C., a catalyst such as trifluoromethane-sulfonyloxysilane is required.
U.S. Pat. No. 4,965,374, Chou, et al., reports that Hertel's condensation method provides alpha-anomer stereoselectively in a 4:1 alpha to beta anomeric ratio of nucleoside products and goes on to describe an improved procedure, based on the Vorbruggen condensation method, that employs a pivotol intermediate of 2-deoxy-2,2-difluoro-3,5-di-O-benzoyl-alpha-D-arabinosyl methanesulfonate. However, Chou's condensation method forms a 1:1 alpha to beta anomer mixture of nucleoside products.
Despite the preceding advances in nucleoside synthesis, there continues to be a need for a stereoselective glycosylation process capable of efficiently producing beta-anomer enriched 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides in high yield and in the absence of a catalyst for reactive and relatively unreactive nucleobase derivatives.
Accordingly, one object of the present invention is to provide a stereoselective glycosylation process for preparing beta-anomer enriched 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides at reaction temperatures below 50.degree. C.
Another object of the present invention is to provide a stereoselective glycosylation process for preparing beta-anomer enriched 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides without the use of a catalyst.
Another object of the present invention is to provide a stereoselective glycosylation process for preparing beta-anomer enriched 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides capable of employing reactive and relatively unreactive nucleobase derivatives.
Another object of the present invention is to provide a stereoselective glycosylation process for preparing beta-anomer enriched 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides in yields higher than those produced by conventional glycosylation procedures.
Yet another object of the present invention is to provide a stereoselective glycosylation process for preparing beta-anomer enriched 2'-deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides offering a means for isolating beta-anomer enriched nucleosides in the form of a crude product or acid addition salt, such as a hydrochloride salt.
Other objects and advantages of the present invention will become apparent from the following description of embodiments.